Introduction
Patients with cancer may receive multiple red blood cell (RBC)
transfusions. While it is true that humans have no way to excrete excess
iron, the high iron levels should block dietary absorption and the
excess iron will eventually be utilized over time. However, these
transfusions lead to iron accumulation that may persist, particularly in
the extrahepatic sites, long after patients have completed their cancer
therapy leading to long-term exposure to toxic forms of iron and the
consequences of this exposure is unknown.1,2 Although
iron accumulation based on liver iron concentration (LIC) accurately
reflects total body iron, it does not reflect movement of toxic ferrous
iron into the heart and endocrine organs. Iron measured by MRI is in the
non-reactive ferric state. Transferrin bound non-reactive ferric iron
enters cells via the transferrin receptor, a process that is shut off if
intracellular iron levels are high. Reactive, ferrous iron is present at
very low levels in circulation but increases dramatically when
transferrin saturation exceeds 60%, which occurs as soon as
erythropoiesis is suppressed by cytotoxic
chemotherapy.3 Ferrous iron can enter cells
non-physiologically through divalent calcium and zinc transporters that
are not regulated by iron. While it is clear from transfusion-dependent
anemias that organ toxicity is related to exposure to ferrous iron, the
presence and impact of exposure to toxic iron is not clear in pediatric
oncology patients.
Toxicities such as endocrine failure and malignant transformation are
related to iron overload (IO)4,5 and overlap with
treatment-induced late effects observed in cancer
survivors.6-8 Considering the existing data that these
are reversible or even preventable by treatment of IO in transfusion
dependent anemia patients,9,10 it would be reasonable
to assume that this would be the case in pediatric oncology patients
despite the lack of corresponding data in this population. Organ
toxicity from iron is related primarily to the amount of reactive iron
in tissue and duration of exposure.11 Due to expected
long-term survival of most pediatric cancer patients, mitigation of
complications is of increased importance. Since these iron-related
complications may take decades to become apparent,
appropriately-designed prospective studies to prove causality are not
feasible. Based on the known risks of long-term exposure to excess iron
from other disorders11 and the current ability to
easily monitor and safely remove excess iron12,
correction of IO in pediatric cancer patients should be a clinical
priority for pediatric survivorship clinics. However, there are many
challenging questions regarding when and how to treat the IO that occurs
in cancer patients.
The Iron Overload Program at Children’s Hospital Los Angeles (CHLA),
which focuses on chronic transfusion dependent anemia and genetic iron
overload syndromes, started an oncology Iron Overload Clinic in 2016.
The diagnostic and treatment approaches are based on our understanding
of principles of iron biology and understanding of the current oncology
treatment. We present a retrospective assessment of organ-specific IO in
a diverse sample of pediatric oncology patients and discuss the results
in the context of the iron toxicity biology.